Title: The Crystal Structure of the Manganese Superoxide Dismutase from Geobacillus stearothermophilus: Parker and Blake (1988) Revisited
Authors: Adams, JJ
Morton, CJ
Parker, MW
Issue Year: 2020
Abstract Highly conserved signalling pathways controlled by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) are central to cellular metabolism and cell proliferation(1,2), and their dysregulation is implicated in the pathogenesis of major human diseases such as cancer and type 2 diabetes. AMPK pathways leading to reduced cell proliferation are well established and, in part, act through inhibition of TOR complex 1 (TORC1) activity. Here we demonstrate reciprocal regulation, specifically that TORC1 directly downregulates AMPK signalling by phosphorylating the evolutionarily conserved residue S367 in the fission yeast AMPK catalytic subunit Ssp2 and AMPK alpha 1 S347 and alpha 2 S345 in the mammalian homologs, which is associated with reduced phosphorylation of activation loop T172. Genetic or pharmacological inhibition of TORC1 signalling led to AMPK activation in the absence of increased AMP/ATP ratios, which under nutrient stress conditions was associated with growth limitation in both yeast and human cell cultures. Our findings reveal fundamental bidirectional regulation between two major metabolic signalling networks and uncover new opportunities for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumour microenvironment.
URI: https://publications.svi.edu.au/publications/7464
Other Identifiers 10.1071/CH19346
Publication type Article